DETERMINATION OF METFORMIN AND INSULIN EFFECT ON HEPATIC TRIGLYCERIDE CONTENT

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。所列机构为中心机构，不一定是研究者机构。肝脏的脂肪浸润可以通过四种不同的机制发生：1）增加脂肪酸到肝脏的流量; 2）增加肝细胞中脂肪酸的合成; 3）减少肝细胞以极低密度脂蛋白形式分泌脂肪酸;和4）减少肝细胞对脂肪酸的氧化。动物模型表明，在胰岛素抵抗的情况下，脂肪酸的从头合成在肝脏脂肪积累中起着重要作用。重要的是，即使在肝细胞胰岛素抵抗的情况下，肝脏中脂肪酸合成的水平也是循环胰岛素水平的函数。人们可以预期，随着胰岛素抵抗和胰岛素水平的升高（由于胰岛细胞输出增加或补充外源性胰岛素），肝细胞脂肪酸合成的速率也会升高。这可能会增加肝脏脂肪含量。 这项研究的研究人员建议检查目前2型糖尿病的两种标准治疗方法对肝脏脂肪含量的影响：二甲双胍和胰岛素。在治疗前和治疗后4个月，将使用质子磁共振波谱法评估肝脏脂肪含量。受试者将被随机分配至两种待研究药物之一，并密切监测与其使用相关的任何药物特异性毒性。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Fatty infiltration of the liver can occur by four distinct mechanisms: 1) increased flux of fatty acids to the liver; 2) increased synthesis of fatty acids in hepatocytes; 3) decreased hepatocyte secretion of fatty acids in the form of very-low-density-lipoprotein and; 4) decreased oxidation of fatty acids by hepatocytes. Animal models suggest that de novo synthesis of fatty acids plays a significant role in the accumulation of liver fat in the setting of insulin resistance. Importantly, the level of fatty acid synthesis in the liver is a function of circulating insulin levels, even in the setting of hepatocyte insulin resistance. One would expect that as insulin resistance worsens and insulin levels rise (either as a result of increased pancreatic islet cell output or supplementation with exogenous insulin), so to would the rate of hepatocyte fatty acid synthesis. This could potentially increase the liver fat content. Investigators in the study propose to examine the effect of two current standard care therapies for type 2 diabetes mellitus on liver fat content: metformin and insulin. Liver fat content will be assessed using proton magnetic resonance spectroscopy before and after 4 months of therapy. Subjects will be randomly assigned to one of the two medication to be studied and closely monitored for any drug-specific toxicities associated with their use.